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Original article
Haplotypes of the inducible nitric oxide synthase gene are strongly associated with exhaled nitric oxide levels in adults: a population-based study
  1. Santosh Dahgam1,
  2. Lars Modig2,
  3. Åsa Torinsson Naluai3,
  4. Anna-Carin Olin1,
  5. Fredrik Nyberg1,4
  1. 1Occupational and Environmental Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
  2. 2Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine, University of Umeå, Umeå, Sweden
  3. 3Department of Medical and Clinical Genetics, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
  4. 4AstraZeneca R&D, Mölndal, Sweden
  1. Correspondence to Dr Fredrik Nyberg, Occupational and Environmental Medicine, Department of Public Health and Community Medicine, University of Gothenburg, PO Box 414, SE-405 30, Gothenburg, Sweden; Fredrik.Nyberg{at}


Background Previous genetic association studies have reported evidence for association of single-nucleotide polymorphisms (SNPs) in the NOS2 gene, encoding inducible nitric oxide synthase (iNOS), to variation in levels of fractional exhaled nitric oxide (FENO) in children and adults. In this study, we evaluated 10 SNPs in the region of chromosome 17 from 26.07 Mb to 26.13 Mb to further understand the contribution of NOS2 to variation in levels of FENO.

Methods In a cohort of 5912 adults 25–75 years of age, we investigated the relationship between NOS2 haplotypes and FENO, and effect modification by asthma.

Results Seven common (frequency ≥5%) haplotypes (H1–H7) were inferred from all possible haplotype combinations. One haplotype (H3) was significantly associated with lower levels of FENO: −5.8% (95% CI −9.8 to −1.7; p=0.006) compared with the most common baseline haplotype H1. Two haplotypes (H5 and H6) were significantly associated with higher levels of FENO: +10.7% (95% CI 5.0 to 16.7; p=0.0002) and +14.9% (95% CI 10.6 to 19.3; p=7.8×10−13), respectively. The effect of haplotype H3 was mainly seen in subjects with asthma (−21.6% (95% CI −33.5 to −5.9)) and was not significant in subjects without asthma (−4.2% (95% CI −8.4 to 0.2)). The p value for interaction between H3 and asthma status was 0.004.

Conclusions Our findings suggest that several common haplotypes in the NOS2 gene contribute to variation in FENO in adults. We also saw some evidence of effect modification by asthma status on haplotype H3.

  • Asthma
  • Complex traits
  • Genetic epidemiology

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